Tumor necrosis factor (TNF-α) is a potent cytokine having pro-inflammatory properties that is released by many cell types when stimulated. Studies have shown a relationship between elevated levels of TNF-α and a variety of diseases including septic shock, hematopoiesis, tumors, and inflammatory disorders of the central nervous system including HIV encephalitis, cerebral malaria, and meningitis. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease also are reportedly associated with enhanced TNF-α levels. See, e.g., Arvin et al., “The Role of Inflammation and Cytokines in Brain Injury,” Neuroscience and Biobehavioral Reviews, Vol. 20, No. 3 (1996), at pp. 445-452. Accordingly, various classes of compounds have been researched and developed to inhibit TNF-α production at both transcriptional and translational levels, e.g., corticosteroids, rolipram (a phosphodiesterase IV inhibitor suppressing TNF-αmRNA synthesis), calphostin, and imidazole-type cytokine suppressing anti-inflammatory drugs (CSAIDs). See, e.g., Dinarello, “Role of Pro- and Anti-Inflammatory Cytokines During Inflammation: Experimental and Clinical Findings, Review, Vol. 0393-974X (1997), at pp. 91-103.
Recently, attention has focussed on the role of Nuclear factor-κB (NF-κB) in the activation pathway that leads to production of TNF-α and other inflammatory cytokines and gene types. Besides TNF-α, NF-κB modulates many genes involved in immune function and inflammation, including IL-2, IL-6, IL-8, IL-2Rα, GM-GSF, intercellular adhesion molecule (ICAM-1), and vascular cellular adhesion molecule-1 (VCAM-1). Thus, inhibition of NF-κB and/or its activation pathway provides a means for treating a wide range of diseases including autoimmune diseases, Alzheimer's disease, atherosclerosis, oncogenesis, and so forth. See, e.g., Baldwin, “The NF-κB and IκB Proteins: New Discoveries and Insights,” Annual Rev. Immunol. Vol. 14 (1996), at pp. 649-81; see also Christman et al., “Impact of Basic Research on Tomorrow's Medicine, The Role of Nuclear Factor-κB in Pulmonary Diseases,” Chest, Vol. 117 (2000), at pp. 1482-87.
Potential inhibitors of NF-κB and/or the NF-κB pathway have been identified as including Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants. IκB is a cytoplasmic protein that controls NF-κB activity by retaining NF-κB in the cytoplasm. IκB is phosphorylated by the IκB kinase (IKK), which has two isoforms, IKK-α (or “IKK-1”) and IKK-β (or IKK-2). Upon phosphorylation of IκB by IKK, NF-κB is rapidly released into the cell and translocates to the nucleus where it binds to the promoters of many genes and up-regulates the transcription of pro-inflammatory genes. Glucocorticoids reportedly inhibit NF-κB activity by two mechanisms, i.e., upregulating IκB protein levels and inhibiting NF-κB subunits. Nitric oxide also reportedly inhibits NF-κB through upregulation of IκB. However, these mechanisms of interaction are complex; for example, production of nitric oxide in lymphocytes reportedly enhances NF-κB activity.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness, bioavailability, and solubility, having fewer side effects, and/or providing the consumer with a choice of options. Particularly in the area of immune response, many individuals respond differently depending upon the type of treatment and chemical agent used. Mechanisms of action continue to be studied to aid in understanding the immune response and in developing compounds effective for treating immune-related disorders.
The present invention provides 4-amino substituted benzoquinoline, benzoquinoxaline, and benzoquinazoline compounds having five-membered heterocycles (e.g., pyrazolyl, imidazolyl, and thiazolyl rings) fused thereto. The compounds are useful as anti-inflammatory agents and/or for treating conditions associated with TNF-α and NF-κB.
Lactam-based tetracyclic compounds useful as antagonists of NMDA (N-methyl-D-aspartate) and AMPA (α-3-hydroxy-5-methylisoxazole-4-propionate) receptors are disclosed in WO 94/07893, Preparation of 5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one AMPA/KA Receptor Antagonist, filed by Aloup et al; and in articles by Mignani, Aloup, et al., “Synthesis and Pharmacological Properties of 5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, a New Competitive AMPA/KA Receptor Antagonist,” Drug. Dev. Res., Vol. 48 (3) (1999), at pp. 121-29, and “An Efficient Preparative Route to Fused Imidazo[1,2-a]-Pyrazin-4-one Derivatives,” Heterocycles, Vol. 50, No. 1 (1999), at pp. 259-267. Compounds such as lactams that are claimed to be useful for blocking excitatory amino acid receptors found in the brain and spinal cord are shown in U.S. Pat. Nos. 5,153,196 and 5,196,421, both assigned to Eli Lilly and Company. Tricyclic compounds having amino-substituents claimed to be useful as brain receptor ligands are disclosed in U.S. Pat. No. 5,182,386, assigned to Neurogen Corp., and in U.S. Pat. Nos. 4,160,097, 4,172,947, 4,191,766, 4,191,767, 4,198,508, 4,200,750, 4,225,724, and 4,236,015, in WO97/19,079, and in S. Ceccarelli et al, “Imidazo[1,2-a]quinoxalin-4-amines: A Novel Class of Nonxanthine A1-Adenosine Receptor Antagonists,” European Journal of Medicinal Chemistry Vol. 33, (1998), at pp. 943-955. To applicants' knowledge, 4-amino substituted tetracyclic compounds according to formula (I) have not been previously described.
The patents and articles cited above are incorporated herein by reference.